Roflumilast N-oxide
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MedKoo CAT#: 329998

CAS#: 292135-78-5

Description: Roflumilast N-oxide is a PDE-4 inhibitor. Roflumilast N-oxide is the active metabolite of roflumilast. Roflumilast (also known as Daxas and Daliresp) acts as a selective, long-acting inhibitor of PDE-4. It has anti-inflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs.

Chemical Structure

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Roflumilast N-oxide
CAS# 292135-78-5
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 329998
Name: Roflumilast N-oxide
CAS#: 292135-78-5
Chemical Formula: C17H14Cl2F2N2O4
Exact Mass: 418.03
Molecular Weight: 419.210
Elemental Analysis: C, 48.71; H, 3.37; Cl, 16.91; F, 9.06; N, 6.68; O, 15.27

Price and Availability

Size Price Availability Quantity
100mg USD 450
200mg USD 750
500mg USD 1450
1g USD 2450
2g USD 4250
5g USD 7250
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Synonym: Roflumilast N-oxide;

IUPAC/Chemical Name: N-(3,5-Dichloro-1-oxopyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide

InChi Key: PCGSQNPMMSALEJ-UHFFFAOYSA-N

InChi Code: InChI=1S/C17H14Cl2F2N2O4/c18-11-6-23(25)7-12(19)15(11)22-16(24)10-3-4-13(27-17(20)21)14(5-10)26-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,24)

SMILES Code: O=C(NC1=C(Cl)C=[N+]([O-])C=C1Cl)C2=CC=C(OC(F)F)C(OCC3CC3)=C2

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, DMF, and ethanol

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Product Data:
Product Data
Instruction:
View handling instruction
Biological target: Roflumilast N-oxide is an inhibitor of phosphodiesterase 4 (PDE4; IC50 = 2 nM). It is selective for PDE4 over PDE1-3 and PDE5 (IC50s = >10,000 nM for all). It reduces TNF-α-induced ICAM-1 and eotaxin levels when used in combination with PGE2 in GM06114 human fetal lung fibroblasts (IC50s = 0.9 and 0.5 nM, respectively). It also reduces bFGF-induced and IL-1β augmented proliferation in the same cells.
In vitro activity: In the PC3 cell line, roflumilast reversed cisplatin (CIS)-induced abnormalities in sperm characteristics, normalized serum testosterone level, ameliorated CIS-induced alterations in testicular and epidydimal weights, and restored normal testicular structure. Roflumilast increased intracellular cAMP levels, PKA, and HO-1 activities; Nrf2, NQO-1 and HO-1 gene expression; improved testicular oxidative stress parameters and inflammatory mediators; and reduced the proapoptotic proteins, caspase-3, Bax and increased Bcl-2. Reference: Food Chem Toxicol. 2021 May;151:112133. https://pubmed.ncbi.nlm.nih.gov/33757793/
In vivo activity: This study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in a model of Parkinson's disease in rats. Rats treated with roflumilast showed an improvement in motor activity and coordination and preservation of dopaminergic neurons in the striatum. Roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Reference: Inflammopharmacology. 2023 Aug 4. https://pubmed.ncbi.nlm.nih.gov/37541971/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 30.0 71.56
DMSO 30.0 71.56
Ethanol 5.0 11.93

Preparing Stock Solutions

The following data is based on the product molecular weight 419.21 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Abdel-Wahab BA, Walbi IA, Albarqi HA, Ali FEM, Hassanein EHM. Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-κB-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling. Food Chem Toxicol. 2021 May;151:112133. doi: 10.1016/j.fct.2021.112133. Epub 2021 Mar 20. PMID: 33757793. 2. Gong S, Chen Y, Meng F, Zhang Y, Li C, Zhang G, Huan W, Wu F. Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis. Cell Prolif. 2018 Oct;51(5):e12474. doi: 10.1111/cpr.12474. Epub 2018 Aug 2. PMID: 30069985; PMCID: PMC6528923. 3. Farid HA, Sayed RH, El-Shamarka ME, Abdel-Salam OME, El Sayed NS. PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson's disease in rats. Inflammopharmacology. 2023 Aug 4. doi: 10.1007/s10787-023-01305-x. Epub ahead of print. PMID: 37541971. 4. Patel P, Patel S, Chudasama P, Soni S, Raval M. Roflumilast ameliorates diabetic nephropathy in rats through down-regulation of JAK/STAT signaling pathway. Naunyn Schmiedebergs Arch Pharmacol. 2023 Jun 15. doi: 10.1007/s00210-023-02535-0. Epub ahead of print. PMID: 37318524.
In vitro protocol: 1. Abdel-Wahab BA, Walbi IA, Albarqi HA, Ali FEM, Hassanein EHM. Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-κB-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling. Food Chem Toxicol. 2021 May;151:112133. doi: 10.1016/j.fct.2021.112133. Epub 2021 Mar 20. PMID: 33757793. 2. Gong S, Chen Y, Meng F, Zhang Y, Li C, Zhang G, Huan W, Wu F. Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis. Cell Prolif. 2018 Oct;51(5):e12474. doi: 10.1111/cpr.12474. Epub 2018 Aug 2. PMID: 30069985; PMCID: PMC6528923.
In vivo protocol: 1. Farid HA, Sayed RH, El-Shamarka ME, Abdel-Salam OME, El Sayed NS. PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson's disease in rats. Inflammopharmacology. 2023 Aug 4. doi: 10.1007/s10787-023-01305-x. Epub ahead of print. PMID: 37541971. 2. Patel P, Patel S, Chudasama P, Soni S, Raval M. Roflumilast ameliorates diabetic nephropathy in rats through down-regulation of JAK/STAT signaling pathway. Naunyn Schmiedebergs Arch Pharmacol. 2023 Jun 15. doi: 10.1007/s00210-023-02535-0. Epub ahead of print. PMID: 37318524.

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1: Patel BS, Rahman MM, Baehring G, Xenaki D, Tang FS, Oliver BG, Ammit AJ. Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells. Am J Respir Cell Mol Biol. 2017 Apr;56(4):532-538. doi: 10.1165/rcmb.2016-0191OC. PubMed PMID: 27997807.

2: Li Q, Wang Y, Liu L, Ma P, Ding L. Pharmacokinetics of Roflumilast and Its Active Metabolite Roflumilast N-Oxide in Healthy Chinese Subjects After Single and Multiple Oral Doses. Eur J Drug Metab Pharmacokinet. 2017 Jun;42(3):371-381. doi: 10.1007/s13318-016-0343-4. PubMed PMID: 27306372.

3: Victoni T, Gicquel T, Bodin A, Daude M, Tenor H, Valença S, Devillier P, Porto LC, Lagente V, Boichot E. Roflumilast n-oxide associated with PGE2 prevents the neutrophil elastase-induced production of chemokines by epithelial cells. Int Immunopharmacol. 2016 Jan;30:1-8. doi: 10.1016/j.intimp.2015.11.019. Epub 2015 Nov 21. PubMed PMID: 26610096.

4: Milara J, Peiró T, Serrano A, Artigues E, Aparicio J, Tenor H, Sanz C, Cortijo J. Simvastatin Increases the Ability of Roflumilast N-oxide to Inhibit Cigarette Smoke-Induced Epithelial to Mesenchymal Transition in Well-differentiated Human Bronchial Epithelial Cells in vitro. COPD. 2015 Jun;12(3):320-31. doi: 10.3109/15412555.2014.948995. Epub 2014 Sep 10. PubMed PMID: 25207459.

5: Milara J, Lluch J, Almudever P, Freire J, Xiaozhong Q, Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014 Aug;134(2):314-22. doi: 10.1016/j.jaci.2014.02.001. Epub 2014 Mar 15. PubMed PMID: 24636089.

6: Milara J, Peiró T, Serrano A, Guijarro R, Zaragozá C, Tenor H, Cortijo J. Roflumilast N-oxide inhibits bronchial epithelial to mesenchymal transition induced by cigarette smoke in smokers with COPD. Pulm Pharmacol Ther. 2014 Aug;28(2):138-48. doi: 10.1016/j.pupt.2014.02.001. Epub 2014 Feb 11. PubMed PMID: 24525294.

7: Victoni T, Gleonnec F, Lanzetti M, Tenor H, Valença S, Porto LC, Lagente V, Boichot E. Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells. PLoS One. 2014 Jan 8;9(1):e85243. doi: 10.1371/journal.pone.0085243. eCollection 2014. PubMed PMID: 24416369; PubMed Central PMCID: PMC3885699.

8: Vecchio D, Acquaviva A, Arezzini B, Tenor H, Martorana PA, Gardi C. Downregulation of NOX4 expression by roflumilast N-oxide reduces markers of fibrosis in lung fibroblasts. Mediators Inflamm. 2013;2013:745984. doi: 10.1155/2013/745984. Epub 2013 Aug 21. PubMed PMID: 24027357; PubMed Central PMCID: PMC3763264.

9: Thappali SR, Varanasi KV, Veeraraghavan S, Vakkalanka SK, Mukkanti K. Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J Mass Spectrom. 2012 Dec;47(12):1612-9. doi: 10.1002/jms.3103. PubMed PMID: 23280750.

10: Höhne K, Schliessmann SJ, Kirschbaum A, Plönes T, Müller-Quernheim J, Tenor H, Zissel G. Roflumilast-N-oxide induces surfactant protein expression in human alveolar epithelial cells type II. PLoS One. 2012;7(7):e38369. doi: 10.1371/journal.pone.0038369. Epub 2012 Jul 16. PubMed PMID: 22815690; PubMed Central PMCID: PMC3398032.

11: Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A, Knaack D, Kley HP, Beume R, Weiss-Haljiti C. The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia. 2012 Oct;55(10):2779-2788. doi: 10.1007/s00125-012-2632-z. Epub 2012 Jul 13. PubMed PMID: 22790061.

12: Knebel NG, Herzog R, Reutter F, Zech K. Sensitive quantification of roflumilast and roflumilast N-oxide in human plasma by LC-MS/MS employing parallel chromatography and electrospray ionisation. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Apr 15;893-894:82-91. doi: 10.1016/j.jchromb.2012.02.038. Epub 2012 Mar 3. PubMed PMID: 22425388.

13: Milara J, Armengot M, Bañuls P, Tenor H, Beume R, Artigues E, Cortijo J. Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro. Br J Pharmacol. 2012 Aug;166(8):2243-62. doi: 10.1111/j.1476-5381.2012.01929.x. PubMed PMID: 22385203; PubMed Central PMCID: PMC3448891.

14: Lahu G, Hünnemeyer A, Diletti E, Elmlinger M, Ruth P, Zech K, McCracken N, Facius A. Population pharmacokinetic modelling of roflumilast and roflumilast N-oxide by total phosphodiesterase-4 inhibitory activity and development of a population pharmacodynamic-adverse event model. Clin Pharmacokinet. 2010 Sep;49(9):589-606. doi: 10.2165/11536600-000000000-00000. PubMed PMID: 20690782.

15: Lahu G, Nassr N, Herzog R, Elmlinger M, Ruth P, Hinder M, Huennemeyer A. Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol. 2011 Apr;51(4):586-93. doi: 10.1177/0091270010370590. Epub 2010 May 13. PubMed PMID: 20466871.

16: Sabatini F, Petecchia L, Boero S, Silvestri M, Klar J, Tenor H, Beume R, Hatzelmann A, Rossi GA. A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulm Pharmacol Ther. 2010 Aug;23(4):283-91. doi: 10.1016/j.pupt.2010.02.004. Epub 2010 Mar 11. PubMed PMID: 20226872.

17: Nassr N, Huennemeyer A, Herzog R, von Richter O, Hermann R, Koch M, Duffy K, Zech K, Lahu G. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol. 2009 Oct;68(4):580-7. doi: 10.1111/j.1365-2125.2009.03478.x. PubMed PMID: 19843061; PubMed Central PMCID: PMC2780283.

18: Lahu G, Huennemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech K. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int J Clin Pharmacol Ther. 2009 Apr;47(4):236-45. PubMed PMID: 19356389.

19: Lahu G, Huennemeyer A, von Richter O, Hermann R, Herzog R, McCracken N, Zech K. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol. 2008 Nov;48(11):1339-49. doi: 10.1177/0091270008321941. Epub 2008 Aug 29. PubMed PMID: 18757786.

20: von Richter O, Lahu G, Huennemeyer A, Herzog R, Zech K, Hermann R. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin Pharmacokinet. 2007;46(7):613-22. PubMed PMID: 17596106.